Inactivation of the CIC-DUX4 oncogene through P300/CBP inhibition, a therapeutic approach for CIC-DUX4 sarcoma.

CIC-DUX4 sarcoma (CDS) is a highly aggressive and metastatic small round type of predominantly pediatric sarcoma driven by a fusion oncoprotein comprising the transcriptional repressor Capicua (CIC) fused to the C-terminal transcriptional activation domain of DUX4. CDS rapidly develops resistance to chemotherapy, thus novel specific therapies are greatly needed. We demonstrate that CIC-DUX4 requires P300/CBP to induce histone H3 acetylation, activate its targets, and drive oncogenesis. We describe the synthetic route to a selective and highly potent P300/CBP inhibitor named iP300w and related stereoisomers, and find that iP300w efficiently suppresses CIC-DUX4 transcriptional activity and reverses CIC-DUX4 induced acetylation. iP300w is active at 100-fold lower concentrations than related stereoisomers or A-485. At low doses, iP300w shows specificity to CDS cancer cell lines, rapidly inducing cell cycle arrest and preventing growth of established CDS xenograft tumors when delivered in vivo. The effectiveness of iP300w to inactivate CIC-DUX4 highlights a promising therapeutic opportunity for CDS.

Can proton therapy improve the therapeutic ratio in breast cancer patients at risk for nodal disease?

OBJECTIVES: Regional node irradiation in patients with invasive breast cancer often results in increased radiation exposure to organs at risk. We evaluated the potential advantages of 3-dimensional conformal photon+proton therapy (3DCX+PT) in treating regional nodes versus photon-electron (3DCRT) or intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Ten left-sided breast cancer patients underwent radiation treatment planning. 3DCX+PT, 3DCRT, and IMRT plans were generated for each patient. RESULTS: There was no significant difference in target coverage between 3DCX+PT and IMRT. However, coverage of level II axillary lymph nodes was inferior with 3DCRT with a median D95 of 45 versus 50 Gy with either IMRT (P=0.0006) or 49.5 CGE with 3DCX+PT (P=0.0033). Internal mammary nodes coverage was also inferior with 3DCRT (median D95 was 42 Gy) compared with 47 Gy with IMRT (P=0.043) or 48.5 CGE with 3DCX+PT (P=0.0068).With 3DCX+PT, left lung V20 and V5 were 31% and 50% versus 36% (P=0.0368) and 70% (P=0.0007) with 3DCRT and 30% (P=0.7328) and 81% (P=0.0002) for IMRT. 3DCX+PT resulted in heart V20 and heart V5 of 0% and 7%, respectively, versus 4% (P=0.0067) and 24% (P=0.0002) with 3DCRT and 21% (P=0.0001), 50% (P=0.0001) with IMRT. The IMRT plans produced significantly higher integral, contralateral lung, and breast doses. CONCLUSIONS: Regional node target coverage was inferior with 3DCRT compared with either IMRT or 3DCX+PT. Organs at risk were exposed to less radiation with 3DCX+PT compared with 3DCRT or IMRT. Proton treatment offered both improved coverage of the regional lymph nodes and decreased dose to the heart, lung, and contralateral normal tissue.

Toxicity analysis of dose escalation from 75.6 gy to 81.0 gy in prostate cancer.

OBJECTIVE: Several randomized trials have demonstrated a biochemical control advantage to an increase from the "conventional" 66 to 70 Gy range to the "high-dose" 75 to 81 Gy range; these trials have also, however, demonstrated a toxicity disadvantage. Our objective was to perform a toxicity analysis of a minor dose escalation (from 75.6 to 81.0 Gy) within this "high-dose" range. METHODS: A total of 189 patients comprised the study population-119 received 75.6 Gy and 70 received 81.0 Gy. Acute, late, and final (at most recent follow-up) gastrointestinal (GI) and genitourinary (GU) toxicity were charted for each group and compared using the χ test. Ordered logit regression analyses were performed on each toxicity end point, using all major demographic, disease, and treatment factors as covariates. RESULTS: The 81.0 Gy group had higher rates of grade 2 acute GU (P < 0.001), late GU (P = 0.001), and late GI (P = 0.082) toxicity, a lower rate of acute GI toxicity (P = 0.002) and no notable differences in final GU (P = 0.551) or final GI (P = 0.194) toxicity compared with the 75.6 Gy group. The ordered logit regression analyses showed that only age (P = 0.019) and radiotherapy dose (P = 0.016) correlated with acute GU toxicity and only radiotherapy dose (P = 0.018) correlated with late GU toxicity. Only intensity modulated radiotherapy use (P = 0.001) correlated with acute GI toxicity; no factors correlated with late GI toxicity or final GU or GI toxicity. CONCLUSIONS: Although some increases in acute and late toxicity rates were observed with even a minor dose escalation from 75.6 to 81.0 Gy, notably no increases in final late GI or GU toxicity rates were observed.

Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma.

PURPOSE: A randomized phase II trial (E1200) was designed to assess toxicities and surgical resection rates in two neoadjuvant gemcitabine-based chemoradiation regimens in patients with borderline resectable pancreatic cancer. The trial was terminated early due to poor accrual. PATIENTS AND METHODS: Patients with borderline resectable adenocarcinomas of the pancreas were enrolled. Arm A patients (n = 10) received gemcitabine 500 mg/m(2) IV weekly for 6 weeks, with radiation to 50.4 Gy followed by surgical resection. Arm B patients (n = 11) received preoperative gemcitabine 175 mg/m(2) on days 1, 5, 29, and 33, cisplatin 20 mg/m(2) on days 1-5 and 29-32, 5-FU 600 mg/m(2) on days 1-5 and 29-32, followed by radiation with continuous infusion 5-FU 225 mg/m(2) for 6 weeks. All patients received adjuvant gemcitabine 1,000 mg/m(2) weekly x 3 for five cycles. RESULTS: Three patients in arm A, and two patients in arm B were resected. Hematologic toxicity was comparable between the two arms except more patients in arm B developed grade 3 or 4 thrombocytopenia than those in arm A. Arm B had fewer grade 1-2 GI toxicities although more patients (45%) experienced grade 3-4 GI toxicity. CONCLUSIONS: This phase II trial showed that both regimens were tolerable, and resectability and survival were comparable to previous studies.

Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer.

Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.